Cancer develops and spreads because of the nature of the tumor and the microenvironment or `soil' in which the tumor is embedded. Multiple myeloma is a blood cancer that results from mutations that accumulate in a plasma cell. Multiple myeloma cells grow in the rich soil of the bone marrow, first very slowly, causing no damage or symptoms, and then more quickly and aggressively, causing degradation of the bone and development of drug resistant clones. The risk of developing myeloma is greater in older individuals and people with high body mass index. These patients also typically have more bone marrow adipose tissue, or fat, than younger or leaner individuals. However, the ways in which bone marrow adipocytes (fat cells) modulate disease progression are not well understood. Thus, we aim to identify new therapeutic avenues to halt multiple myeloma progression by targeting the interactions between myeloma cells and bone marrow adipocytes to lead to better therapeutics for patients. Due to the potentially inflammatory nature of bone marrow adipose tissue, and its ability to act as a source of fatty acids and adipokines, we wanted to explore how bone marrow adipose tissue affects myeloma tumor cells. Our cell culture studies suggest bone marrow adipocytes induce drug resistance in myeloma cells through proteins called fatty acid-binding proteins 4 and 5 (FABP4 and FABP5). In Specific Aim 1 of this proposal, we will analyze how bone marrow adipocytes contribute to myeloma by using novel, three-dimensional (3D), tissue engineered cancer models. Compared to two- dimensional (2D) cultures, 3D cultures much more realistically recapitulate what happens in the human body. The tissue engineered models are made from silk scaffolds, bone marrow adipocytes, and cancer cells. By growing myeloma cells in these 3D mini-bone environments, we can determine how myeloma cells change in response to adipocytes and discover new ways to target this interaction. In Specific Aim 2 of our proposal, we will use mouse models to study bone marrow adipocyte and myeloma crosstalk. Our mouse models recapitulate very closely how tumors grow in patients. We will test how increasing or removing bone marrow adipocytes in mice affects tumor growth and drug resistance, and we will test specifically the role of FABP4 and FABP5 in this process. We will use these in vitro and in vivo models, which we have already developed and optimized in our lab, to better understand how cancer hijacks the bone marrow niche for its own purposes. Our long-term goal is to understand molecules and mechanisms driving multiple myeloma growth in the bone marrow. This proposal feeds into that by interrogating a novel part of the cellular ?soil? (the bone marrow adipocyte), in which tumor cells, or ?seeds? land and grow. In sum, our research will identify feedback loops between host and cancer cells, indicate mediators of this interaction, and propose paradigm-shifting concepts to guide the development of new anti-myeloma therapies.